Pathology within the neural systems that mediate fear has been proposed as a mechanism for many forms of anxiety disorders. The experience of fear is a normal component of coordinated set responses to danger. Glucocorticoids secreted during stress may play an important role in sustaining fear during a protracted threat and make the organism more reactive to novel threats in the future. Increased reactivity to threatening situations is adaptive when it improves the individual's ability to escape danger. However, when increased fearfulness persists in the absence of a clear threat, a maladaptive state of anxiety may ensue. Our long term goal is to identify brain structures that mediate increased fear when glucocorticoids are elevated and elucidate the neural mechanisms of heightened fear during glucocorticoid excess. Both the amygdala and bed nuclei of stria terminalis (BNST) are limbic structures crucial for the expression of fear and the neuropeptide corticotropin releasing factor (CRF) is upregulated in both structures when glucocorticoids are elevated. Administration of glucocorticoids directly into the amygdala increases fear;however the behavioral effects of elevated glucocorticoids in the BNST are currently unknown. Glucocorticoid administration into the amygdala increases CRF mRNA in this structure and systemic administration of the selective CRF1 receptor antagonist antalarmin abolishes heightened fear when glucocorticoids are elevated in the amygdala. These findings suggest that CRF mediates increased fearfulness when glucocorticoids are elevated in the amygdala however;the site of action for CRF is currently unknown. The focus of the proposed project is to determine the role of the amygdala and BNST in heightened fear when glucocorticoids are chronically elevated. We will determine the direct effects of elevated corticosterone in the BNST on fear and determine whether these effects are mediated by CRF (Aim 1). We will accomplish this aim by implanting micropellets of corticosterone in the oval or fusiform nuclei of the BNST prior to assessing fear using the open field test and the elevated plus maze. Next, we will determine the role of CRF in mediating the behavioral effects of elevated corticosterone in the BNST by systemic administration of antalarmin prior to behavioral testing. In addition, we will determine the role of CRF in the amygdala and BNST in mediating increased fear observed when circulating glucocorticoids are chronically elevated (Aim 2). We will accomplish this aim by administering corticosterone for one week then microinjecting antalarmin into the BNST (oval or fusiform nuclei) or the amygdala (basolateral or central nuclei) prior to assessing fear. A clear understanding of the neural mechanisms mediating the transition from normal fear to anxiety may provide the rationale for developing strategies for the prevention and treatment of anxiety disorders. PUBLIC HEALTH RELEVANCE: Anxiety disorders affect 40 million Americans each year. It is possible that brain mechanisms that regulate normal fear responses become hyperactive in the development of many anxiety disorders. The overall objective of the current research is to understand the transition from normal fear to pathological anxiety in order to provide the rationale for better treatment and prevention of anxiety disorders.